Project Summary A central goal of infectious disease research is to identify the genes that determine an individual?s susceptibility to parasites. Biomedical research has made substantial progress towards this goal by establishing molecular and genetic approaches for detecting alleles associated with parasite resistance and host health. Pursuing these alleles across many organisms, including humans, has revealed an underlying problem: an allele may strongly predict parasite resistance in one environment but not others, or against one parasite strain but not others. This context-dependence might explain why genomic surveys have rarely been able to identify alleles that consistently explain disease susceptibility in humans. In addition, there is immense genetic diversity for parasite resistance in host populations, and this diversity is not represented in the few inbred lab lines used to identify alleles in model organisms. Therefore, to gain a general understanding of the alleles that matter for parasite resistance, we must account for the genetic diversity and environmental complexity present in the natural settings in which hosts encounter their parasites. In the next five years, research in my lab will address this need by characterizing the genetic basis of parasite resistance across genetic and environmental contexts using diverse host and parasite genotypes sampled from nature. My lab group is well-positioned for this work: we have expertise in the nematode Caenorhabditis elegans and its most prevalent natural parasite, the microsporidia Nematocida parisii. This powerful model system enables us to quickly and cheaply perform highly replicated experiments and genomic analyses to examine genetic variants across contexts. Recent efforts to collect wild C. elegans isolates and parasite strains have provided us with the broad sampling of natural variation necessary for our goal. Here, I propose to 1) characterize the alleles that contribute to parasite resistance in natural populations using high-throughput phenotyping, genome-wide association surveys, and high- resolution quantitative trait mapping based on public collections of fully-sequenced wild C. elegans genotypes (>300) and recombinant inbred lines based on multiple wild parents. I then propose to use experimental evolution, phenotype mapping, and transgenic host lines to: 2) evaluate the impact of parasite genotype on the expression of genetic variation for parasite resistance, and 3) examine the sensitivity of resistance alleles to relevant environmental variation, specifically in microbial diet and population density. This proposed work forms the foundation of my research program targeted at establishing general frameworks for identifying the diversity of alleles that can determine parasite resistance and evaluating their contribution to host health in real world settings. This work will support efforts to use genetic data to predict the health of individuals and populations.